Treprostinil production

ABSTRACT

The present invention is directed to a novel method for preparing a synthetic intermediate for treprostinil via a stereoselective alkyne addition reaction. Also described are methods of preparing treprostinil comprising the alkyne addition reaction described herein as well as novel intermediates useful for synthesis prostacyclin derivatives, such as treprostinil.

The present application claims the benefit of U.S. provisionalapplication No. 61/351,115 filed Jun. 3, 2010, which is incorporatedherein by reference in its entirety.

The present application relates to a process for producing prostacyclinderivatives, such as Treprostinil, and novel intermediate compoundsuseful in the process.

(+)-Treprostinil (also known as UT-15) is the active ingredient inRemodulin®, a commercial drug approved by FDA for the treatment ofpulmonary arterial hypertension (PAH). It was first described in U.S.Pat. No. 4,306,075. Treprostinil is a stable analog of prostacyclin(PGI₂) belonging to a class of compounds known as benzindeneprostacyclins, which are useful pharmaceutical compounds possessingactivities such as platelet aggregation inhibition, gastric secretionreduction, lesion inhibition, and bronchodilation.

U.S. Pat. No. 5,153,222 describes use of treprostinil for treatment ofpulmonary hypertension. Treprostinil is approved for the intravenous aswell as subcutaneous route, the latter avoiding potential septic eventsassociated with continuous intravenous catheters. U.S. Pat. Nos.6,521,212 and 6,756,033 describe administration of treprostinil byinhalation for treatment of pulmonary hypertension, peripheral vasculardisease and other diseases and conditions. U.S. Pat. No. 6,803,386discloses administration of treprostinil for treating cancer such lung,liver, brain, pancreatic, kidney, prostate, breast, colon and head-neckcancer. U.S. patent application publication No. 2005/0165111 disclosestreprostinil treatment of ischemic lesions. U.S. Pat. No. 7,199,157discloses that treprostinil treatment improves kidney functions. U.S.Pat. No. 7,879,909 discloses treprostinil treatment of neuropathic footulcers. U.S. publication No. 2008/0280986 discloses treprostiniltreatment of pulmonary fibrosis, interstitial lung disease withtreprostinil and asthma. U.S. Pat. No. 6,054,486 discloses treatment ofperipheral vascular disease with treprostinil. U.S. patent applicationpublication No. 2009/0036465 discloses combination therapies comprisingtreprostinil. U.S. publication No. 2008/0200449 discloses delivery oftreprostinil using a metered dose inhaler. U.S. Pat. Nos. 7,417,070,7,384,978 and 7,544,713 as well as U.S. publications Nos. 2007/0078095,2005/0282901, and 2008/0249167 describe oral formulations oftreprostinil and other prostacyclin analogs as well as their use fortreatment of a variety of conditions. U.S. provisional application No.61/354,949 filed Jun. 15, 2010 discloses the use of orally administeredtreprostinil for treatment of Raynaud's phenomenon, systemic sclerosisand digital ischemic lesions.

Treprostinil and other prostacyclin derivatives have been prepared asdescribed in Moriarty, et al in J. Org. Chem. 2004, 69, 1890-1902, Drugof the Future, 2001, 26(4), 364-374, U.S. Pat. Nos. 4,306,075,6,441,245, 6,528,688, 6,700,025, 6,765,117, 6,809,223 and US PublicationNo. 2009/0163738. The entire teaching of these documents areincorporated herein by reference in their entirety. The methodsdescribed in these patent documents, however, do not describe a feasibleproduction method for producing stereochemically pure treprostinilbecause, for example, the methods require the use of expensive reagentsand tedious chromatographic purification techniques. Therefore, there isa need in the art for an economical, efficient and simplified method forpreparing trepostinil and its synthetic intermediates.

SUMMARY

One embodiment relates to a method of preparing a synthetic intermediateof trepostinil represented by the following structural formula:

wherein:

P₁ is an alcohol protecting group;

R is —(CH₂)_(n)X;

X is H, phenyl, —CN, —OR₁ or COOR₁;

R₁ is an alkyl, THP or TBDMS; and

-   -   n is 1, 2 or 3.

The method comprises reacting a compound represented by structuralformula (I):

with a compound represented by structural formula (a):

wherein R and P₁ are as described above for structural formula (A).

Another embodiment is to a method of preparing treprostinil comprisingreaction 1, and optionally comprising one or more reactions 2-9according to Scheme 2.

Yet another embodiment is a compound of formula (1):

wherein R is (CH₂)_(m)CO₂R₁, m is 1, 2 or 3, and

-   -   R₁ is an alkyl group, THP, TBDMS or a substituted or        unsubstituted benzyl group.

And yet another embodiment is a compound represented by structuralformula (A):

wherein:

-   -   P₁ is an alcohol protecting group;    -   wherein R is (CH₂)_(m)CO₂R₁, m is 1, 2 or 3, and    -   R₁ is an alkyl group or a substituted or unsubstituted benzyl        group.

And yet another embodiment is a compound represented by structuralformula (4):

wherein:

each of P₁ and P₂ is an alcohol protecting group;

wherein R is (CH₂)_(m)CO₂R₁, m is 1, 2 or 3, and

R₁ is an alkyl group, or a substituted or unsubstituted benzyl group.

And yet another embodiment is a compound represented by structuralformula (5):

wherein:

each of P₁ and P₂ is an alcohol protecting group;

wherein R is (CH₂)_(m)CO₂R₁, m is 1, 2 or 3, and

R₁ is an alkyl group, or a substituted or unsubstituted benzyl group.

And yet another embodiment is a compound represented by structuralformula (6):

wherein:

P₁ is an alcohol protecting group;

wherein m is 1, 2 or 3, and

R₁ is an alkyl group, or hydrogen.

DETAILED DESCRIPTION

Unless otherwise specified, “a” or “an” means “one or more”.

The present application is directed to methods of preparing treprostiniland synthetic intermediates useful of synthesizing treprostinil as wellto synthetic intermediates themselves. The present application is alsodirected to methods of preparing treprostinil or a pharmaceuticallyacceptable salt thereof comprising the alkyne addition reactiondescribed herein. Preferred treprostinil salts may include the sodiumsalt and the diethanolamine salt (see, e.g., U.S. Pat. No. 7,417,070).

In some embodiments, the present application is directed to a method ofpreparing a synthetic intermediate (A) of treprostinil through astereoselective alkyne addition reaction.

One embodiment is directed to a novel method (reaction 1) for preparinga compound of structural formula (A) comprising the step of reacting analdehyde of structural formula (1) with an alkyne of structural formula(a):

wherein:

-   -   P₁ is an alcohol protecting group;    -   R is —(CH₂)_(n)X;    -   X is H, phenyl, —CN, —OR₁ or COOR₁;    -   R₁ is an alkyl, THP, TBDMS or a substituted or unsubstituted        benzyl group; and    -   n is 1, 2 or 3.

As used herein, “an alcohol protecting group” is a functional group thatprotects the alcohol group from participating in reactions that areoccurring in other parts of the molecule. Suitable alcohol protectinggroups are well known to those of ordinary skill in the art and includethose found in T. W. Greene, Protecting Groups in Organic Synthesis,John Wiley & Sons, Inc. 1981, the entire teachings of which areincorporated herein by reference. Exemplary alcohol protecting groupsinclude, but are not limited to, actetyl, benzoyl, benzyl,p-methoxyethoxymethyl ether, methoxymethyl ether, dimethoxytrityl,p-methoxybenzyl ether, trityl, silyl ether (e.g., trimethylsilyl (TMS),tert-butyldimethylsilyl (TBMDS), tert-butyldimethylsilyloxymethyl (TOM)or triisopropylsilyl (TIPS) ether), tetrahydropyranyl (THP), methylether and ethoxyethyl ether (EE).

An alkyl group may be a saturated straight-chain or branched aliphaticgroup. For example, an alkyl group may a (C1-C6)alkyl, (C1-C5)alkyl,(C1-C4)alkyl or (C1-C3)alkyl. Examples of alkyl groups include methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,pentyl, iso-amyl, and hexyl. An alkyl group is optionally substitutedwith an alkyl, a cycloalkyl (e.g., cyclopentyl or cyclohexyl), an aryl(e.g., phenyl), or heteroaryl group.

A phenyl group may be optionally substituted with one or moresubstituents, which may be independently selected from the groupconsisting of —NO₂, —CN, halogen (e.g., —F, —Cl, —Br or —I),(C1-C3)alkyl, halo(C1-C3)alkyl, (C1-C3)alkoxy and halo(C1-C3)alkoxy.

A substituted benzyl group may be optionally substituted at one or moremeta, ortho or para positions with one or more substituents, which maybe independently selected from the group consisting of —NO₂, —CN,halogen (e.g., —F, —Cl, —Br or —I), (C1-C3)alkyl, halo(C1-C3)alkyl,(C1-C3)alkoxy and halo(C1-C3)alkoxy.

In one embodiment, for reaction 1 described above, P₁ may be THP.

In another embodiment, R may be selected from the group consisting ofmethyl, benzyl, —CH₂COOMe, —CH₂COOCH₂Ph, THP and TBDMS. Alternatively, Ris methyl.

In yet another embodiment, R is methyl and P₁ is THP.

In yet another embodiments, R is —CH₂CO₂R₁, wherein R₁ is an alkylgroup, such as a straight or branched C1-C5 alkyl group, or asubstituted or unsubstituted benzyl group, and P₁ is tetrahydrofuranyl(THP), benzyl, 2,4-dinitrobenzyl, methoxymethyl (MOM),tertiarybutyldimethylsilyl (TBDMS), tertiarybutyldiphenylsilyl (TBDPS)or triethylsilyl (TES).

When reaction 1 is carried out in the presence of a chiral inducingagent, the reaction may yield a product having predominantly Sconfiguration of the hydroxyl group at the benzylic carbon position. A“chiral inducing agent” is a compound that is used to createstereoselectivity at a chiral center. For example,(+)-N-methylephiderine may be used as the chiral inducing agent forreaction 1 described above. In one embodiment, at least 70%, 80%, 90%,95%, 97%, 98%, 99%, 99.5%, 99.9% or 100% by weight of the product ofreaction 1 is represented by structural formula (A), i.e., the compoundprepared by reaction 1 has at least 40%, 60%, 80%, 90%, 94%, 96%, 98%,99.0%, 99.8% or 100% chiral purity.

In some embodiments, reaction 1 may be carried out in the presence of abase and a zinc reagent. An exemplary zinc reagent includes zinctriflate (Zn(OTf)₂). Suitable bases that may be used include, forexample, an alkali carbonate, an alkali hydroxide, an amine and anammonium hydroxide. In some embodiments, Et₃N may be preferred as thebase.

In some embodiments, reaction 1 as described in any one of the foregoingembodiments may be carried out in an organic solvent. Suitable organicsolvents include, for example, ethereal solvents (e.g., diethyl ether,methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane anddimethoxyethane), aromatic solvents (e.g., benzene and toluene),chlorinated solvents (e.g., methylene chloride and 1,2-dichloroethane),alcohol solvents (e.g., methanol, ethanol, 2-propanol),dimethylformamide, dimethyl sulfoxide and acetonitrile. In one specificembodiment, reaction 1 may be carried out in toluene.

U.S. Pat. Nos. 6,700,025, 6,809,223, 6,528,668 and 6,441,245 describe amethod, which may be used for preparing some of the compounds ofstructural formula (A). This method, depicted in Scheme 1, however,includes 3 reaction steps.

Compared to the prior art method, reaction 1 of the present inventionmay have one or more of the following advantages: (1) reaction 1 hashigh diastereoselectivity, wherein the product with greater than 95%chiral purity can be obtained. (2) the prior method requires 3-stepsynthesis; whereas the method (reaction 1) of the present invention onlyhas a single step, which shortens the number of chemical steps needed;eliminates the tedious column chromatographic purifications involved inthe extra two steps and saves manpower and large volume of solvents. (3)reaction 1 may be carried out at room temperature, and therefore nocryogenic reactors are needed; (4) reaction 1 is less expensive than theprior art method as the prior art method involves the use of expensivereagents as needed in the Corey asymmetric reduction. (5) reaction 1 isan eco-friendly method as it does not require the use of obnoxiousborane-dimethyl sulfide complex in the Corey asymmetric reduction.

In some embodiments, the compound of structural formula (A) may besubsequently converted to a prostacyclin derivative such as treprostinilaccording to Scheme 2, reaction steps 2-9.

In Scheme 2, R and P₁ are as described above for structural formula (A);P₂ is an alcohol protecting group; and m is 1, 2, or 3.

The present application may be also directed to a method of preparing aprostacyclin derivative represented by structural formula (IX) or apharmaceutically acceptable salt thereof comprising reaction 1. In someembodiments, the method may also optionally include one or more stepsselected from the group consisting of reaction 2, reaction 3, reaction4, reaction 5, reaction 6, reaction 7, reaction 8 and reaction 9 shownin Scheme 2 in conjunction with reaction 1 to make the prostaglandinderivative (IX). For example, the method comprises the steps of reaction1 and reaction 3. Alternatively, the method may comprise the steps ofreaction 1, reaction 3, reaction 4, reaction 5 and reaction 6. Inanother alternative, the method may comprise the steps of reaction 1,reaction 8 and reaction 9. In yet another alternative, the method forpreparing treprostinil comprises the steps of reaction 1, reaction 2,reaction 3, reaction 4, reaction 5, reaction 6, reaction 7, reaction 8and reaction 9.

As used herein, a “pharmaceutically acceptable salt” refers to a saltthat is useful in preparing a pharmaceutical composition and isgenerally safe, non-toxic and neither biologically nor otherwiseundesirable pharmaceutical use.

Compounds with basic groups, such as amine groups, can formpharmaceutically acceptable salts with pharmaceutically acceptableacid(s). Suitable pharmaceutically acceptable acid addition salts of thecompounds of the invention include salts of inorganic acids (such ashydrochloric acid, hydrobromic, phosphoric, metaphosphoric, nitric, andsulfuric acids) and of organic acids (such as, acetic acid,benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic,glycolic, isethionic, lactic, lactobionic, maleic, malic,methanesulfonic, succinic, p-toluenesulfonic, and tartaric acids).Compounds with acidic groups such as carboxylic acids can formpharmaceutically acceptable salts with pharmaceutically acceptablebase(s). Suitable pharmaceutically acceptable basic salts includeammonium salts, alkali metal salts (such as sodium and potassium salts)and alkaline earth metal salts (such as magnesium and calcium salts).Compounds with a quaternary ammonium group also contain a counteranionsuch as chloride, bromide, iodide, acetate, perchlorate and the like.Other examples of such salts include hydrochlorides, hydrobromides,sulfates, methanesulfonates, nitrates, maleates, acetates, citrates,fumarates, tartrates [e.g. (+)-tartrates, (−)-tartrates or mixturesthereof including racemic mixtures], succinates, benzoates and saltswith amino acids such as glutamic acid. A particularly preferred salt isthe diethanolamine salt of treprostinil.

In one embodiment, the prostacyclin derivative (e.g., treprostinil)prepared according to the methods described herein may have at least40%, 60%, 80%, 90%, 94%, 96%, 98%, 99.0%, 99.8% or 100% chiral purity.

In one embodiment, the prostacyclin derivative is treprostinilrepresented by structural formula (IX-1) (i.e., m=1 for structuralformula (IX).

In one embodiment, for structural formulas (I)-(VI) and (A), R may beselected from the group consisting of methyl, benzyl, —CH₂COOMe,—CH₂COOCH₂Ph, THP and TBDMS. More specifically, R is methyl.

In another embodiment, for structural formulas (I)-(V), (A) and (a), P₁is THP.

In yet another embodiment, for structural formulas (II) and (III), P₂ isTBDMS.

In another embodiment, for reactions depicted in Scheme 2, R is methyl,P₁ is THP, P₂ is TBDMS and m is 1.

In one embodiment, for methods of preparing a prostacyclin derivativedescribed herein, specific conditions and reagents for reaction 1 are asdescribed above.

For reaction 2 depicted in Scheme 2 above, compound (A) is reacted withan alcohol protecting reagent to form the compound of structural formula(II). An “alcohol protecting reagent” is a reagent that converts a —OHgroup to —OP₂. In one embodiment, the alcohol protecting reagent isTBDMSCl.

In one embodiment, reaction 2 is carried out in the presence of a base.Suitable base can be used includes, but is not limited to, an alkalicarbonate, an alkali hydroxide, an amine and an ammonium hydroxide. Morespecifically, the base is an amine. Even more specifically, the base isa mixture of imidazole and dimethylaminopyridine (DMAP).

Reaction 2 can be carried out in a suitable solvent or a solventmixture. In one embodiment, reaction 2 is carried out in an organicsolvent, such as ethereal solvents (e.g., diethyl ether, methyltert-butyl ether, tetrahydrofuran, 1,4-dioxane and dimethoxyethane),aromatic solvents (e.g., benzene and toluene), chlorinated solvents(e.g., methylene chloride and 1,2-dichloroethane), alcohol solvents(e.g., methanol, ethanol, 2-propanol), dimethylformamide, dimethylsulfoxide and acetonitrile. In one embodiment, the solvent is methylenechloride (CH₂Cl₂).

For reaction 3 depicted in Scheme 2, the compound of structural formula(II) is converted to the compound of structural formula (III) through acobalt-mediated cyclization reaction. More specifically, the cyclizationreaction is carried out in the presence of CO₂(CO)₈.

In one embodiment, reaction 3 is carried out in an organic solvent or amixture of organic solvents. Suitable organic solvents include, but arenot limited to, ethereal solvents (e.g., diethyl ether, methyltert-butyl ether, tetrahydrofuran, 1,4-dioxane and dimethoxyethane),aromatic solvents (e.g., benzene and toluene), chlorinated solvents(e.g., methylene chloride and 1,2-dichloroethane), alcohol solvents(e.g., methanol, ethanol, 2-propanol), dimethylformamide, dimethylsulfoxide and acetonitrile. More specifically, reaction 3 is carried outinitially in CH₂Cl₂ followed by removal of the solvent by distillation.The reaction is subsequently carried out in acetonitrile.

For reaction 4 depicted in Scheme 2, the compound of structural formula(III) is hydrogenated with H₂ to form the compound of structural formula(IV). In one embodiment, the hydrogenation reaction is carried out inthe presence of a hydrogenation catalyst. More specifically, thehydrogenation reaction is carried out in the presence of Pd/C. Inanother embodiment, the hydrogenation reaction is carried out in thepresence of a base, such as a alkali carbonate (e.g., K₂CO₃).

Reaction 4 can be carried out in an organic solvent, such as etherealsolvents (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran,1,4-dioxane and dimethoxyethane), aromatic solvents (e.g., benzene andtoluene), chlorinated solvents (e.g., methylene chloride and1,2-dichloroethane), alcohol solvents (e.g., methanol, ethanol,2-propanol), dimethylformamide, dimethyl sulfoxide and acetonitrile.More specifically, the reaction is carried out in EtOH.

For reaction 5, the compound of structural formula (IV) is reacted witha reducing agent to form the compound of structural formula (V). A“reducing agent” is a reagent that can convert a carbonyl functionalgroup to an alcohol functional group. Suitable reducing agents can beused include, but are not limited to, NaBH₄ and LiAlH₄. Morespecifically, the reducing agent is NaBH₄. In one embodiment, reaction 5is carried out in the presence of a base, such as an alkali hydroxide(e.g. NaOH). Reaction 5 can be carried out in an organic solvent, suchas those described above. More specifically, the reaction is carried outin EtOH.

For reaction 6, the compound of structural formula (V) is reacted with astrong acid, such as p-toluenesulfonic acid (pTsOH), TFA, TfOH, orhydrochloric acid, to form the compound of structural formula (VI). Morespecifically, the acid is pTsOH. Reaction 6 can be carried out in anorganic solvent, such as those described above. More specifically, thesolvent is MeOH.

For reaction 7, the compound of structural formula (VI) is reacted withPh₂PH in the presence of a base. In one embodiment, the base isalkyllithium. More specifically, the base is nBuLi. Reaction 7 can becarried out in an organic solvent. Exemplary organic solvents aredescribed above. In one embodiment, reaction 7 is carried out intetrahydrofuran (THF).

For reaction 8, the compound of structural formula (VII) is reacted withX₁(CH₂)_(m)CN to form the compound of structural formula (VIII), whereinX₁ is a leaving group and m is 1, 2 or 3. A “leaving group” is a moietythat can easily be displaced by a nucleophile. For example, a leavinggroup is a halide (e.g., —Cl, —Br, —I), a sulfonate group (e.g.,MeSO₂O—, CF₃SO₂O—, CH₃C₆H₄SO₂O—, or C₆H₅SO₂O—). More specifically, X₁ is—Cl and m is 1.

In one embodiment, reaction 8 is carried out in the presence of a base,such as an alkali carbonate (e.g., K₂CO₃).

Reaction 8 can be carried out in an organic solvent, such as thosedescribed above. More specifically, the solvent is acetone.

For reaction 9, the compound of structural formula (VIII) is reactedwith a base, such as an alkali hydroxide (e.g., NaOH). The reaction canbe carried out in an organic solvent, such as those described above. Inone embodiment, the reaction is carried out EtOH.

Also included in the present invention is the prostacyclin derivativesrepresented by structural formula (IX) (e.g., treprostinil) prepared bymethods described herein.

In some embodiments, a prostacyclin derivative represented by structuralformula (IX), such as treprostinil, or a pharmaceutically acceptablesalt thereof may be prepared using one or more reactions from Scheme 3:

In Scheme 3, R₁ may be an alkyl group or a substituted or unsubstitutedbenzyl group, and P₁ are as described above for structural formula (A);P₂ is an alcohol protecting group; and m is 1, 2, or 3.

Compound (7) in Scheme 3 corresponds to the prostacyclin derivativerepresented by structural formula (IX) earlier in the disclosure,compound (2) in Scheme 3 corresponds to the compound of structuralformula (A) earlier in the disclosure, while Step 2 in corresponds toreaction 1 earlier in the disclosure.

In some embodiments, a method of preparing a prostacyclin derivativerepresented by structural formula (IX) or a pharmaceutically acceptablesalt thereof may comprising Step 2 of Scheme 3. The method may alsooptionally include one or more steps selected from the group consistingof Step 1, Step 3, Step 4, Step 5 and Step 6 shown in Scheme 3 inconjunction with Step 2 to make the prostaglandin derivative (IX). Forexample, the method comprises Step 2 and Step 3. Alternatively, themethod may comprise Step 2, Step 3 and Step 4. In another alternative,the method may comprise the steps of Step 2, Step 5 and Step 6. Inanother alternative, the method may comprise Step 1 and Step 2. In yetanother alternative, the method for preparing treprostinil may compriseStep 1, Step 2, Step 3, Step 4, Step 5 and Step 6.

The reactions of scheme 3 may be particularly useful for R is—(CH₂)_(m)CO₂R₁, wherein m=1, 2 or 3 and R₁ is an alkyl group, such as astraight or branched C1-C5 alkyl group, or a substituted orunsubstituted benzyl group. Compared to prior art methods, such as thosedisclosed in U.S. Pat. Nos. 6,700,025, 6,809,223, 6,528,668 and6,441,245, the method of Scheme 3 may include fewer steps for preparinga prostacyclin derivative represented by structural formula (IX).

Step 1 of Scheme 3 may be performed by reacting compound 1 with R₂COOR₁,wherein R₂ may be a leaving group such as halogen, e.g. Cl, I, or Br,tosylate, mesylate or triflate, and R₁ is an alkyl group or asubstituted or unsubstituted benzyl group. In some embodiments, thereaction may be carried out in the presence of a base, which may be analkali carbonate, such as K₂CO₃. In some embodiments, the base may bepotassium tertiary butoxide (t-BuOK), sodium hydride (NaH), sodiumhydroxide (NaOH), lithium hydroxide (LiOH), potassium hydroxide (KOH)etc. The reaction may be carried out in a number of solvents includingbutanone, propanone, N,N-dimethyl formamide (DMF), dimethoxyethane(DME), dimethylsulfoxide (DMSO), tetrahydrofuran (THF), toluene andacetone.

Step 2 of Scheme 3 may be performed as described above for reaction 1 ofscheme 2.

Step 3 of Scheme 3 may be performed by compound (A) with an alcoholprotecting reagent to form the compound of structural formula (4). An“alcohol protecting reagent” is a reagent that converts a —OH group to—OP₂. In some embodiments, P₂ may be tert-butyldimethylsilyl (TBDMS),tertiarybutyldiphenylsilyl (TBDPS), triethylsilyl (TES) ortriphenylmethyl (trityl group). The respective alcohol protectivereagents may be TBDMSCl or TBDMSOTf for TBDMS, TESCl for TES, TBDPSClfor TBDPS and tritylchloride for trityl. In some embodiments, TBDMS maybe preferred as P₂ and TBDMSCl may be preferred as the alcoholprotecting reagent. Chemical formula of exemplary protective reagents ispresented below.

In one embodiment, Step 3 of Scheme 3 may be carried out in the presenceof a base. Suitable base that may be used includes, but is not limitedto, an alkali carbonate, an alkali hydroxide, an amine and an ammoniumhydroxide. In one specific embodiment, the base may an amine, such as ofimidazole, 4-dimethylaminopyridine (DMAP) or a mixture thereof.

Step 3 of Scheme 3 may be carried out in a suitable solvent or a solventmixture. In one embodiment, Step 3 of Scheme 3 may be carried out in anorganic solvent, such as ethereal solvents (e.g., diethyl ether, methyltert-butyl ether, tetrahydrofuran, 1,4-dioxane and dimethoxyethane),aromatic solvents (e.g., benzene and toluene), chlorinated solvents(e.g., methylene chloride and 1,2-dichloroethane), dimethylformamide,dimethyl sulfoxide and acetonitrile. In one embodiment, the solvent maybe methylene chloride (CH₂Cl₂).

Step 4 of Scheme 3 may be performed by converting the compound ofstructural formula (4) to the compound of structural formula (5). Insome embodiments, such conversion may be performed by a cobalt-mediatedcyclization reaction. Such cyclization reaction may be carried out, forexample, in the presence of CO₂(CO)₈.

In one embodiment, Step 4 of Scheme 3 may be carried out in an organicsolvent or a mixture of organic solvents. Suitable organic solventsinclude, but are not limited to, ethereal solvents (e.g., diethyl ether,methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane anddimethoxyethane), aromatic solvents (e.g., benzene and toluene),chlorinated solvents (e.g., methylene chloride and 1,2-dichloroethane),alcohol solvents (e.g., methanol, ethanol, 2-propanol),dimethylformamide, dimethyl sulfoxide and acetonitrile. In someembodiments Step 4 of Scheme 3 may be carried out in1,2-dimethoxyethane. followed by removal of the solvent by distillation.

In some embodiments, Step 4 may be carried out using from about 2 to 15mol % or from 3 to 12 mol % or from 5 to 10 mol % or any subrange withinthe above stated ranges of CO₂(CO)₈. In some embodiments, Step 4 may becarried out under atmosphere of carbon monoxide using from about 2 to 15mol % or from 3 to 12 mol % or from 5 to 10 mol % or any subrange withinthe above stated ranges of CO₂(CO)₈. Such conditions may save costand/or avoid laborious column chromatography and hence save timecompared to stoichiometric Pauson-Khand cyclization such as the oneused, for example, in U.S. Pat. No. 6,765,117.

In some embodiments, the reaction of Step 4 may be carried out underatmospheric pressure. Yet in some embodiments, the reaction of step ofStep 4 may be carried at a pressure that is higher than the atmosphericpressure. The use of the elevated pressure may make the reaction of Step4 go faster compared the reaction under the atmospheric pressure. Insome embodiments, the reaction of Step 4 may be carried out at apressure ranging from 10 psi to 250 psi or from 20 psi to 250 psi orfrom 20 psi to 200 psi or any subrange within these ranges.

Step 5 of Scheme 3 may be performed by hydrogenating the compound ofstructural formula (5) to form a hydrogenated compound of formula (6) or(6′). The hydrogenation reaction may involve reacting the compound ofstructural formula (5) with H₂. In some embodiments, the hydrogenationreaction may be carried out in the presence of a hydrogenation catalyst.Such hydrogenation catalyst may comprise a metal hydrogenation catalyst,such as Pd. In some embodiments, the hydrogenation catalyst may be Pd/C.In some embodiments, the hydrogenation reaction may be carried out inthe presence of a base, which may be a alkali carbonate, such as K₂CO₃.

Step 5 of Scheme 3 may be carried out in an organic solvent, such asethereal solvents (e.g., diethyl ether, methyl tert-butyl ether,tetrahydrofuran, 1,4-dioxane and dimethoxyethane), aromatic solvents(e.g., benzene and toluene), chlorinated solvents (e.g., methylenechloride and 1,2-dichloroethane), alcohol solvents (e.g., methanol,ethanol, 2-propanol), dimethylformamide, dimethyl sulfoxide andacetonitrile.

When R₁ is an alkyl group Step 5 may result in the hydrogenated compoundof structural formula (6):

When R₁ is a substituted of unsubstituted benzyl group Step 5 may resultin the hydrogenated compound of structural formula (6′):

which has its benzyl group cleaved as the result of hydrogenation.

Step 6 of Scheme 3 may be performed by converting the hydrogenatedcompound represented by structural formula (6) or (6′) to a compoundrepresented by structural formula (7) or (IX). In some embodiments, theconversion of Step 6 may be performed in the presence of a reducingagent, which may be used for the reduction of the ketone to alcohol onthe cyclopentyl ring. The reducing agent may be, for example, NaBH₄,NaCNBH₃ or LiBH₄. In some embodiments, the reducing agent may be usedtogether with a base, which may be used for hydrolysis of the estergroup to acid. The base may be, for example, NaOH, KOH, LiOH or Ba(OH)₂.In some embodiments, step 6 may be carried in the presence of an acid,which may be used to obtain a free acid from the ester group after itshydrolysis and/or to remove the protection group P₁ from the side chain.In some embodiments, the acid may be, for example, HCl, acetic acid,formic acid, trifluoroacetic acid, para-toluene sulfonic acid, diluteH₂SO₄, dilute HNO₃ or a polymer bound acidic resin, such as Amberlyst-15or Dowex 50WX-X8. Solvents, which may be used for Step 6's conversion,may include water and/or organic solvents, such as alcohols, for exampleethanol. In some embodiments, Step 6 may be performed in the presence oftwo or more of the reducing agent, the base and the acid. In someembodiments, Step 6 may be carried out in the presence of all three ofthe reducing agent, the base and the acid.

Step 6 may allow performing one or more of the following in a singlepot: reduction of the ketone of compound (6) to alcohol of compound (7),hydrolysis of the ester group of compound (6) to a free acid of compound(7) and removal of the P₁ protective group of compound (6).

For example, conversion of compound of structural formula (6), when R₁is an alkyl group, the conversion reaction may accomplish cleaving ofthe protective group P₁ and ester hydrolysis of R to a free acid in asingle pot. This conversion may also include reduction of the ketone ofcompound (6) to alcohol of compound (7).

The present invention also relates to intermediates for synthesis aprostacyclin derivative represented by structural formula (IX), such ascompounds of formulas (2), (3), (4), (5) and (6, 6′) in Scheme 3.

The invention is further illustrated by, though in no way limited to,the following examples.

Example 1 Preparation of Chiral Benzyl Alcohol (A-1)

A 50-mL, two-necked, round-bottom flask equipped with a mechanicalstirrer was charged with zinc triflate (2.16 g, 0.0059 mol) and(+)-N-methylephiderine (0.814 g, 0.0045 mol) in toluene (10 mL). To thismixture triethyl amine was added (0.459 g, 0.0045 mol) and thisgelatinous mixture was stirred at ambient temperature for 30-60 minutes.To this mixture was then treated with a solution of alkyne (1.08 g,0.0045 mol) in toluene (1 mL), stirred at ambient temperature for 15minutes followed by solution of aldehyde (0.250 g, 0.0014 mol). Progressof the reaction was monitored by TLC (completion of the reaction wasmonitored by thin layer chromatography (TLC) using a thin layer silicagel plate; eluent: 20% ethyl acetate in hexanes). After stirring themixture for 3 h TLC indicated completion of reaction. At this stagereaction mixture was quenched by slow addition of saturated ammoniumchloride (10 mL). This was stirred for 5-10 minutes and organic layercontaining desired compound was separated. Aqueous layer was washed withethyl acetate (10 mL). The combined organic layers were washed withbrine (15 mL), dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo to obtain a crude product (2.0 g). The crudeproduct was purified by column chromatography using 250-400 mesh silicagel. A solvent gradient of ethyl acetate in hexanes (5-20%) was used toelute the product from the column. All fractions containing the desiredproduct were combined and concentrated in vacuo to give pure chiralbenzyl alcohol A-1 (0.360 g, ˜87%) compound was characterized by ¹H, ¹³CNMR, IR, LCMS and chiral HPLC data. ¹H NMR (CDCl₃, 300 MHz): δ 0.87 (t,3H), 1.18-1.86 (m, 17H), 2.28 (dt, 1H), 2.34-2.45 (m, 2H), 3.40-3.53 (m,1H), 3.54-3.62 (m, 1H), 3.63-3.75 (m, 1H), 3.81 (s, 3H, OCH₃), 3.83-3.92(m, 1H), 4.62-4.66 (m, 1H), 4.89-5.05 (m, 2H), 5.59-5.61 (merged two s,1H), 5.91-6.04 (m, 1H), 6.85-6.82 (d, 1H), 7.20-7.26 (m, 1H), and7.31-7.36 (m, 1H); ¹³C NMR (CDCl₃, 75 MHz): δ 14.13, 14.18, 14.98,15.56, 19.96, 21.14, 22.71, 24.77, 25.34, 25.57, 29.51, 31.17, 31.23,32.07, 32.19, 32.69, 33.51, 33.94, 35.13, 55.86, 60.49, 62.12, 62.18,62.82, 75.36, 75.89, 80.20, 80.53, 86.97, 87.42, 97.31, 98.06, 110.63,114.80, 119.18, 119.27, 125.86, 127.44, 127.50, 137.15, 140.78, 157.68;IR: 3411, 2230, 1638, 1259, 1133, 1023, 755 cm⁻¹; MS (m/z): [M+Na]⁺437.35.

Example 2 Preparation of treprostinil (IX-1)

Treprostinil can be prepared according to Scheme 4. Exemplary reactionconditions for making the chiral benzyl alcohol (compound A-1) aredescribed in Example 1. Exemplary conditions for other reactionsdepicted in Scheme 3 are as described in U.S. Pat. Nos. 6,700,025,6,809,223, 6,528,668 and 6,441,245. The entire teaching of all thesedocuments are incorporated herein by reference.

Example 3 Preparation of Treprostinil

The inventors have developed a stereoselective route for the synthesisof treprostinil (7) starting from aldehyde (1) and side chain (SCiv).This route may involve direct stereoselective addition of an alkyne tostarting 2-Allyl-3-[(carbomethoxy)methoxy]benzaldehyde (2) andillustrates the synthetic utility of catalytic a Pauson-KhandCyclization (PKC) for the synthesis of a drug substance, treprostinil(7, UT-15). O-alkylation of the readily available3-hydroxy-2-allylbenzaldehyde (Step 1->2) with methylbromoacetateprovided the required starting material (2) to accomplish thissynthesis. The steps in the synthesis may involve a stereoselectiveaddition of an alkyne, and an efficient stereoselection effected in thePKC of a benzoenyne under the agency of a protective group P₁, such asbenzylic OTBDMS group. This protective group can serve as a temporarystereodirecting group and may be conveniently removed via hydrogenolysisconcomitantly in the catalytic hydrogenation of the enone PKC product.At the final step, reduction, P₁ cleavage and ester hydrolysis may beaccomplished in one pot to obtain desired prostaglandin analog product,such as treprostinil (7).

The advantage of the present chemistry may include, but not limitedto: 1) direct stereoselective addition of alkyne to aldehyde; 2) thisroute may also eliminate the need of four steps in the prior artsynthesis of prostacyclin derivatives disclosed, for example, inMoriarty et al (U.S. Pat. No. 6,765,117). In particular, the presentroute may eliminate one or more of the following steps of the prior artsynthesis (U.S. Pat. No. 6,765,117):

1) Grignard addition step (compound 5-compound 6 in U.S. Pat. No.6,765,117);

2) PCC oxidation step (compound 6-compound 7 in U.S. Pat. No.6,765,117);

3) Chiral reduction step, aka as Corey reduction (compound 7-compound 8in U.S. Pat. No. 6,765,117);

4) demethylation of phenyl methyl ester (compound 13-compound 14 in U.S.Pat. No. 6,765,117).

The present synthesis scheme may not only shorten the number of chemicalsteps to obtain treprostinil but also eliminate the tedious columnchromatographic purifications required in the prior art methods, such asthe one in U.S. Pat. No. 6,765,117 at intermediate steps. Suchelimination of the prior art chromatographic purifications maysignificantly save manpower and large volumes of solvents. For example,the prior art route of U.S. Pat. No. 6,765,117 has 15 steps and requireschromatographic purifications on all them but one (compound 11-compound12). The present synthesis has only 6 steps and may includechromatographic purification in at most three steps (steps 2, step 3 andstep 4).

The present synthesis scheme may enable performing the reactions at roomtemperature without the need for cryogenic reactors, which are requiredin the prior art methods, such as the one in U.S. Pat. No. 6,765,117.For example, the prior art route of U.S. Pat. No. 6,765,117 requirescryogenic reactors in chiral reduction step (compound 7-compound 8) andin demethylation of phenyl methyl ester (compound 13-compound 14).

The present synthesis does not involve use of expensive reagents whichare required in the prior art methods, such as the one in U.S. Pat. No.6,765,117. For example, the prior art route of U.S. Pat. No. 6,765,117in the chiral reduction step (compound 7-compound 8) used startingcompound (B) for Corey reagent (B+C), which is an expensive reagent.Corey reagent (B+C) itself is also an expensive reagent.

This report provides the experimental details on the synthesis oftreprostinil (7) below.

Step 1: 2-Allyl-3-[(carbomethoxy)methoxy]benzaldehyde (2)

TABLE 1 Name MW Amount mol Aldehyde (1) 162.18 2.5 g 0.015methylbromoacetate 152.97 2.5 g 0.016 K₂CO₃ 138.21 6.3 g 0.045 AcetoneNA 50 ml NA

Procedure: A 100-mL round-bottom flask equipped with a magnetic stirrerand stir bar was charged with a solution of3-hydroxy-2-allylbenzaldehyde (1) (2.5 g in 50 mL acetone),methylbromoacetate (2.5 g, 1.10 eq.) and powdered potassium carbonate(6.3 g, 3.0 eq.). The mixture was stirred at 40° C. for four hours andprogress of reaction was monitored by TLC (Note 1). After completion ofthe reaction, the suspension was filtered and the filtrate wasevaporated in vacuo to afford a crude semi-solid mass. This was slurriedin 30 mL of hexanes and stirred for 15 minutes. A solid crashed out ofthe hexanes and was collected by filtration to obtain compound (2) as anoff-white solid; yield 3.48 g (99%), mp 46-47° C. The structure wasconsistent with spectral data. IR (neat) cm⁻¹: 3084, 2761, 1735, 1692;¹H NMR (CDCl₃, 300 MHz) δ 3.78 (s, 3H), 3.91 (d, 2H, J=6 Hz), 4.71 (s,2H), 4.98 (m, 2H), 6.03 (m, 1H), 6.96 (d, 1H, J=8 Hz), 7.33 (dd, 1H, J=8Hz), 7.52 (d, 1H, J=8 Hz); ¹³C NMR (CDCl₃, 75 MHz) δ 28.32, 52.37,66.01, 115.75, 117.05, 123.73, 127.55, 131.73, 135.40, 136.58, 156.23,169.09, 192.08; MS: (M+1) 235.41.

Note 1: Completion of the reaction was monitored by TLC using a thinlayer silica gel plate; eluent: 20% ethyl acetate in hexanes.

Step 2: Preparation of Chiral Benzyl Alkynol (3)

TABLE 2 Name MW Amount mol Aldehyde (2) 234.25 0.50 g 0.0026 Alkyne sidechain (Sciv) 238.37 1.57 g 0.0065 Zinc triflate 363.51 3.17 g 0.0087(+)-N-Methylephedrine 179.26 1.22 g 0.0068 Triethylamine 101.19 0.68 g0.0068 Toluene NA 10 ml NA

Procedure: A 50-mL, two-necked, round-bottomed flask equipped with amagnetic stirrer and stir bar was charged with zinc triflate (3.17 g,0.0087 mol) and (+)-N-methylephedrine (1.22 g, 0.0068 mol) in toluene (5mL). To this mixture triethylamine was added (0.68 g, 0.0068 mol) andthis gelatinous mixture was stirred at ambient temperature for 1-2 h. Tothis mixture was then added a solution of alkyne (1.57 g, 0.0065 mol) intoluene (4 mL), stirred at ambient temperature for 15-30 minutesfollowed by addition of a solution of aldehyde (2) (0.50 g, 0.0026 molin 1-2 mL toluene). Progress of the reaction was monitored by TLC (Note1). After stirring the mixture at room temperature for 16 h, TLCindicated completion of reaction. The reaction mixture was quenched byslow addition of water (10 mL). This was stirred for 5-10 minutes andorganic layer containing desired compound was separated. The aqueouslayer was extracted with ethyl acetate (10 mL). The combined organiclayers were washed with brine (10 mL), dried over anhydrous sodiumsulfate, filtered and the filtrate concentrated in vacuo to obtain acrude product. The crude product was purified by column chromatographyusing 250-400 mesh silica gel. A solvent gradient of ethyl acetate inhexanes (5-20%) was used to elute the product from the column. Allfractions containing the desired pure product were combined andconcentrated in vacuo to give pure chiral benzyl alkynol (3, 700 mg,−70%). The structure was consistent with spectral data.

¹H NMR (CDCl₃, 300 MHz) δ 0.84 (t, 3H, J=6 Hz), 1.25-1.82 (m, 17H), 2.28(t, 1H, J=6 Hz), 2.34-2.42 (m, 2H), 3.42-3.52 (m, 1H), 3.61-3.74 (m,3H), 3.78 (s, 3H), 3.81-3.95 (m, 1H), 4.61 (s, 2H), 4.68 (m, 1H),4.94-5.01 (m, 2H), 5.62 (br s, 1H), 5.97-6.07 (m, 1H), 6.76 (d, 1H, J=8Hz), 7.16-7.27 (m, 1H), 7.38-7.43 (m, 1H); ¹³C NMR (CDCl₃, 75 MHz)84.75, −4.38, −3.49, 14.12, 14.16, 14.84, 15.52, 18.06, 18.38, 20.04,20.24, 22.70, 24.76, 25.25, 25.56, 25.72, 25.94, 29.67, 31.22, 31.28,32.05, 32.11, 32.65, 33.41, 34.01, 35.08, 52.22, 62.36, 62.84, 63.09,66.04, 75.41, 76.44, 76.68, 80.83, 81.22, 85.57, 86.01, 97.31, 98.85,110.89, 114.80, 119.77, 119.82, 125.56, 127.11, 127.16, 136.46, 136.52,142.66, 142.73, 155.83, 169.68; MS: (M+Na) 495.6.

Note 1: Completion of the reaction was monitored by thin layerchromatography (TLC) using a thin layer silica gel plate; eluent: 20%ethyl acetate in hexanes.

Step 3: Preparation of Chiral Benzylalkynyl tert.-butyldimethylsilylether (4)

TABLE 3 Name MW Amount Mol Chiral benzylalkynol 472.62 0.680 g 0.0014t-butyldimethylsilyl chloride 150.73 0.282 g 0.0018 Imidazole 68.0 0.127g 0.0018 4-(Dimethylamino)pyridine 122.17 0.167 g 10 mol %Dichloromethane NA 30.0 mL NA

Procedure: A 50-mL, two-necked, round-bottomed flask equipped with amagnetic stirrer and stir bar was charged with a solution of chiralbenzylalkynol (3) (0.680 g, 0.0014 mol) in dichloromethane (30 mL) underargon. To this solution, imidazole (0.127 g, 0.0018 mol) and4-(dimethylamino)pyridine (0.176 g, 10 mol %) were added while stirringat room temperature. The stirring was continued until a clear solutionwas obtained. To this solution t-butyldimethylsilyl chloride (0.282 g,0.0018 mol) was added slowly while stirring. The reaction mixture wasstirred at room temperature for approximately 3-4 h (Note 1). Thereaction was quenched by addition of a saturated ammonium chloridesolution (10 mL). The organic layer was separated and washed with brine(10 mL), dried over sodium sulfate and concentrated in vacuo. The crudeproduct was purified by column chromatography using 250-400 mesh silicagel and eluted with a gradient solvent of ethyl acetate in hexanes(2-12%). The fractions containing the desired compound were evaporatedin vacuo to yield benzyl alkynyl t-butyldimethylsilyl ether (4) as acolorless, viscous liquid (0.800 g, 94%). The structure was consistentwith spectral data.

¹H NMR (CDCl₃, 300 MHz) δ 0.07-0.13 (four merged s, 6H), 0.83 (merged t,3H), 0.89-0.91 (two merged s, 9H), 1.24-1.84 (m, 10H), 2.18-2.34 (m,2H), 3.39-3.69 (m, 3H), 3.78 (s, 3H), 3.81-3.91 (m, 1H), 4.55-4.56 (m,1H), 4.62 (s, 2H), 4.96-4.98 (m, 2H), 5.57 (br s, 1H), 5.92-6.01 (m,1H), 6.66 (d, 1H, J=8 Hz), 7.17 (two dd, 1H, J=8 Hz), 7.30 (d, 1H, J=8Hz).

Note 1: Completion of the reaction was monitored by TLC using a thinlayer silica gel plate; eluent: 20% ethyl acetate in hexanes.

Step 4: Preparation of Tricyclicenone (5)

TABLE 4 Name MW Amount Mole Benzyl alkynyl t-butyldimethylsilyl ether(4) 584.65 0.100 g 0.00017 Octacarbonyldicobalt 341.95 0.0030 5 mol %1,2-Dimethoxyethane NA 10 ml NA

Procedure: A 50-mL round-bottomed flask equipped with a magnetic stirrerand stir bar was charged with a solution of benzylalkynyltert.-butyldimethylsilyl ether (4) (0.10 g) in 1,2-DME (10 mL), and wasdegassed by bubbling argon through the solution for 2-3 minutes. To thissolution was added CO₂(CO)₈ (0.003 g) and the mixture was stirred atroom temperature under an atmosphere of carbon monoxide (CO, usingballoon). After 30 minutes the reaction mixture was heated to 60-65° C.using an oil bath for 6 h (Note 1). After cooling to room temperature,1,2-DME (solvent) was evaporated in vacuo to yield a crude, gummycompound that was purified by flash chromatography on silica gel using5-20% ethyl acetate in hexanes. Fractions containing the desiredcompound were collected and evaporated in vacuo to yield tricyclic enone(5) (102 mg, 83%). The structure was consistent with spectral data. IR(neat) cm, 1: 2928, 1728, 1702; ¹H NMR (CDCl₃, 300 MHz) δ 0.02-0.13 (m,6H), 0.80 (merged s, 9H), 0.81-0.88 (m, 1H). 1.18-2.61 (m, 16H), 2.71(dd, 1H, J=6 Hz), 3.32-3.60 (m, 4H), 3.79 (merged s, 3H), 3.80-3.92 (m,1H), 4.56 (merged d, 1H), 4.60 (merged s, 2H), 5.47 and 5.53 (two s,1H), 6.63, 1H, J=8 Hz), 6.97 (dd, 1H, J=8 Hz), 7.19 (dd, 1H, J=8 Hz);¹³C NMR (CDCl₃, 75 MHz) 8 −4.20, 4.08, 14.17, 18.15, 20.13, 22.69,24.84, 25.71, 31.27, 32.14, 33.29, 33.93, 42.19, 52.34, 62.86, 65.50,76.68, 97.24, 110.19, 123.28, 125.74, 127.31, 137.52, 137.95, 155.18,169.44, 209.60.

Note 1: Completion of reaction was monitored by TLC using a thin layersilica gel plate; eluant: 20% ethyl acetate in hexanes. After 3 h, TLCshowed presence of starting material. At this stage extra 5 mol % cobaltcatalyst was added at room temperature and reaction was again heated at60-65° C. until completion (total reaction time 6 h)

Step 5: Preparation of Tricyclic Ketone (6)

TABLE 5 Name MW Amount Mole Tricyclic enone (5) 614.90 0.10 g NAPalladium on charcoal NA 0.01 g NA (50% wet) Potassium carbonate NA0.010 NA Methanol NA 10.0 ml NA Water NA 1.00 ml NA

Procedure: A 200-mL round-bottom flask equipped with a magnetic stirrerand stir bar was charged with a solution of tricyclic enone (5) (0.10 g)in methanol (10.0 mL) and aqueous K₂CO₃ (0.010 g in 1.0 mL water). Tothis solution, Pd/C (0.010 g, 50% wet) was added while stirring at roomtemperature. The reaction vessel was evacuated and pressurized withhydrogen gas using a balloon. The reaction mixture was hydrogenated atballoon pressure overnight (˜16 h) at ambient temperature. After 16 h,the reaction was monitored by TLC, infra-red (IR) and proton NMR (Note1). At this stage the reaction mixture was filtered through a pad ofCelite (˜4 g). The Celite pad was washed with methanol (˜50 mL). Thecombined filtrates were evaporated in vacuo to give crude tricyclicketone (6) and the crude product was purified by column chromatographyusing 250-400 mesh silica gel. A solvent gradient of ethyl acetate inhexanes (5-35%) was used to elute the product from column. The fractionscontaining desired product were evaporated in vacuo to yield tricyclicketone (6) (0.035 g, 44%). IR (neat) cm⁻¹ 2929, 1736, 1679; ¹H NMR(CDCl₃, 300 MHz) δ 0.87 (br t, 3H), 1.21-3.12 (m, 27H), 3.42-3.53 (m,1H), 3.55-3.68 (m, 1H), 3.79 (s, 3H), 3.86-3.95 (m, 1H), 4.61-4.69 (m,1H), 4.64 (merged s, 2H), 6.53-6.56 (m, 1H), 6.74-6.81 (m, 1H),7.06-7.08 (m, 1H).

Note 1: Completion of the hydrogenation was checked by monitoring thechange in the IR carbonyl stretch frequency [starting material(tricyclic enone)˜1728 cm⁻¹, product (tricyclic ketone)−1736 cm⁻¹ andproton NMR. The reaction mixture was evacuated and then purged withargon. A small aliquot of reaction mixture was sampled, filtered througha short pad of Celite, and the filtrate was evaporated in vacuo to givea thick, oily compound. The IR of the oily compound was checked forabove mentioned carbonyl stretch frequency. Completion of reaction wasmonitored by TLC using a thin layer silica gel plate; eluent: 40% ethylacetate in hexanes.

Step 6: Preparation of Treprostinil (7)

TABLE 6 Name MW Amount Mole Tricyclic ketone (6) 486.65 0.0035 g 0.00006Sodium hydroxide 40.0 0.030 g 0.00073 Sodium borohydride 37.8 0.004 g0.00012 Methanol NA 5.0 ml NA Water NA 1.0 ml NA HCl NA (10%) 4-5 ml NA

Procedure: A 200-mL round-bottom flask equipped with a magnetic stirrerand stir bar was charged with a solution of tricyclic ketone (6) (0.035g) in methanol (5.0 mL). It was cooled to −5° C. and aqueous sodiumhydroxide solution (0.030 g, 15 eq, dissolved in 1.0 mL water) was addedwhile stirring. The reaction mixture was stirred for 30 minutes and thensodium borohydride (0.004 g in 1.0 mL water) was added and stirring wascontinued at −5° C. for 2 h. This was slowly allowed to warm to roomtemperature and stirred overnight (˜16 h). The reaction mixture wasquenched carefully by dropwise addition of 10% hydrochloric acid (˜4-5mL) until pH 2-3. Then the mixture was concentrated in vacuo and to thiswater (10 mL) and ethyl acetate (10 mL) were added and stirred for 5-10minutes. The organic layer was separated and washed with brine (10 mL),dried over sodium sulfate and concentrated in vacuo to obtain UT-15 (7)as an off-white solid (0.021 g). The compound was characterized byspectral data and HPLC. The ¹HNMR and HPLC of the samples were comparedwith reference UT-15 and were identical; ¹H NMR (CDCl₃, 300 MHz) δ 0.90(t, 3H, 6 Hz), 1.05-1.78 (m, 13H), 2.85-2.85-2.98 (m, 1H), 2.03 2.12 (m,1H), 2.21-2.32 (m, 1H), 2.45-2.53 (m, 1H), 2.61-2.81 (m, 3H), 3.52 (brs, 1H), 3.58-3.69 (m, 1H), 4.62 (s, 2H), 6.69 (d, 1H, J=8 Hz), 6.78 (d,1H, J=8 Hz), 7.04 (dd, 1H, J=8 Hz).

Example 4 Preparation 2-Ally-3-(carbomethoxy)benzyloxybenzaldehydeReaction Scheme:

Experimental Preparation of 2-Allyl-3-benzyloxybenzaldehyde (3)

TABLE 7 Name Mol Wt Amount mol 2-Allyl-3-hydroxybenzaldehyde 162.18 1.00g 0.006 Benzyl bromoacetate 229.08 1.53 g 0.006 Potassium carbonate138.21 3.30 g 0.024 Acetone NA 20 mL NA

Experimental Procedure

To a solution of 2-allyl-3-hydroxybenzaldehyde (1) (1.00 g, 0.006 mol)in acetone (20 mL) was added powdered potassium carbonate (3.30 g) andbenzyl bromoacetate (2) (1.53 g, 0.006 mol). The reaction mixture wasstirred at 40° C. (oil bath temperature) for 5 h. The reaction mixturewas checked by tlc (Note 1). The reaction was complete. The mixture wasfiltered, and the filtrate was concentrated in vacuo to get crudeviscous liquid. The crude product was purified by silica gel columnchromatography using a mixture of ethyl acetate and hexanes (4-10%) toget colorless viscous liquid (1.73 g, 88.7%). ¹H NMR (CDCl₃, 300 Hz)3.89 (m, 2H), 4.74 (s, 2H), 4.95-5.00 (m, 2H), 5.22 (s, 2H), 5.97-6.06(m, 1H), 6.97 (m, 1H), 7.29-7.34 9m, 6H), 7.54 (m, 1H).

Note 1: Completion of the reaction was monitored by thin layerchromatography (TLC) using a thin layer silica gel plate; eluent: 10%ethyl acetate in hexanes.

Step 2: Preparation of Chiral Benzyl Alkynol (4)

TABLE 8 Name a. W Amount mol Aldehyde 312.00 0.250 g 0.0008 Alkyne sidechain (Sciv) 238.37 3.00 g 0.0025 Zinc triflate 363.51 1.20 g 0.0030(+)-N-Methylephedrine 179.26 0.460 g 0.0025 Triethylamine 101.19 0.810 g0.0025 Toluene NA 10 mL NA

Procedure:

A 50-mL, two-necked, round-bottomed flask equipped with a magneticstirrer and stir bar was charged with zinc triflate (1.20 g, 0.0030 mol)and (+)-N-methylephedrine (0.460 g, 0.0025 mol) in toluene (5 mL). Tothis mixture triethylamine was added (0.810 g, 0.0025 mol) and thisgelatinous mixture was stirred at ambient temperature for 1-2 h. To thismixture was then added a solution of alkyne (3.00 g, 0.0025 mol) intoluene (4 mL), stirred at ambient temperature for 15-30 minutesfollowed by addition of a solution of aldehyde (0.250 g, 0.0008 mol in1-2 mL toluene). Progress of the reaction was monitored by TLC (Note 1).After stirring the mixture at room temperature for 2 h, TLC indicatedcompletion of reaction. The reaction mixture was quenched by slowaddition of water (10 mL). This was stirred for 5-10 minutes and organiclayer containing desired compound was separated. The aqueous layer wasextracted with ethyl acetate (10 mL). The combined organic layers werewashed with brine (10 mL), dried over anhydrous sodium sulfate, filteredand the filtrate concentrated in vacuo to obtain a crude product. Thecrude product was purified by column chromatography using 250-400 meshsilica gel. A solvent gradient of ethyl acetate in hexanes (5-20%) wasused to elute the product from the column. All fractions containing thedesired pure product were combined and concentrated in vacuo to givepure chiral benzyl alkynol (370 mg, 84%). The structure was consistentwith spectral data. ¹H NMR (CDCl₃, 300 MHz) δ 0.84 (τ, 3H), 1.24-1.75(m, 17H), 2.24-2.30 (m, 2H), 3.43-3.47 (m, 1H), 3.65-3.84 (m, 2H),3.86-3.87 (m, 1H), 4.63-4.67 (m, 3h), 4.95-4.97 (m, 2H), 5.21 (s, 2H),5.60 (m, 1H), 5.95-6.04 (m, 1H), 6.70 (m, 1H), 7.18-7.36 (m, 8H).

Note 1: Completion of the reaction was monitored by thin layerchromatography (TLC) using a thin layer silica gel plate; eluent: 20%ethyl acetate in hexanes.

Additional Embodiments

-   1. A method of preparing a compound represented by the following    structural formula:

comprising reacting a compound represented by the following structuralformula:

with a compound represented by the following structural formula:

wherein:

-   -   P₁ is an alcohol protecting group;    -   R is —(CH₂)₁X;    -   X is H, phenyl, —CN, —OR₁ or COOR₁;    -   R₁ is an alkyl, THP, TBDMS or a unsubstituted or substituted        benzyl group; and    -   n is 1, 2 or 3.

-   2. The method of embodiment 1, wherein R is methyl.

-   3. The method of embodiment 1, wherein R is CH₂CO₂C₂H₅.

-   4. The method of embodiment 1, wherein R is CH₂CO₂CH₃.

-   5. The method of embodiment 1, wherein R is CH₂CO₂Bn.

-   6. The method of embodiment 1, wherein P₁ is tetrahydropyranyl    (THP).

-   7. The method of embodiment 1, wherein P₁ is tert-butyldimethylsilyl    (TBDMS), tertiarybutyldiphenylsilyl (TBDPS), triethylsilyl (TES) or    triphenylmethyl (trityl group).

-   8. The method of embodiment 7, wherein P₁ is tert-butyldimethylsilyl    (TBDMS).

-   9. The method of embodiment 1, wherein the reaction is carried out    in the presence of chiral inducing agent.

-   10. The method of embodiment 9, wherein the chiral inducing ligand    is (+)-N-methylephederin.

-   11. The method of embodiment 1, wherein the reaction is carried out    in the presence of a base and a zinc reagent.

-   12. The method of embodiment 11, wherein the base is triethylamine.

-   13. The method of embodiment 12, wherein the zinc reagent is zinc    triflate.

-   14. A method of preparing a compound represented by the following    structural formula:

or a pharmaceutically acceptable salt thereof, comprising:

reacting a compound represented by structural formula (I):

with a compound represented by structural formula (a):

to form a compound represented by structural formula (A):

wherein:

-   -   P₁ is an alcohol protecting group;    -   R is —(CH₂)₁X;    -   X is H, phenyl, —CN, —OR₁ or COOR₁;    -   R₁ is an alkyl group, THP, TBDMS or a substituted or        unsubstituted benzyl group; and    -   n is 1, 2 or 3.

-   15. The method of embodiment 14, further comprising:    -   (1) reacting the compound of structural formula (A) with an        alcohol protecting group to form a compound represented by        structural formula (II):

-   -   (2) converting the compound of structural formula (II) to a        tricyclic compound represented by structural formula (III):

-   -   (3) hydrogenating the tricyclic compound of structural        formula (III) to form a hydrogenated tricyclic compound        represented by structural formula (IV):

-   -   (4) reacting the compound of structural formula (IV) with a        reducing agent to form a compound represented by structural        formula (V):

-   -   (5) deprotecting the compound of structural formula (V) to form        a compound represented by structural formula (VI):

-   -   (6) converting the compound represented by structural        formula (VI) to a compound represented by structural formula        (VII):

-   -   (7) reacting the compound represented by structural        formula (VII) with X₁(CH₂)_(m)CN to form a compound represented        by structural formula (VIII):

and

-   -   (8) hydrolyzing the compound of Structural Formula (VIII) to        form the compound represented by Structural Formula (IX),    -   wherein:        -   P₂ is an alcohol protecting group;        -   m is 1, 2 or 3; and        -   X₁ is a leaving group.

-   16. The method of embodiment 14, wherein R is methyl.

-   17. The method of embodiment 14, wherein R is CH₂CO₂C₂H₅.

-   18. The method of embodiment 14, wherein P₁ is tetrahydrofuranyl    (THP).

-   19. The method of embodiment 14, wherein the compound of structural    formula (IX) is tresprostinil represented by the following    structural formula:

-   20. The method of embodiment 14, wherein the reaction of the    compound of structural formula (I) and the compound of structural    formula (a) is carried out in the presence of a chiral inducing    agent.-   21. The method of embodiment 20, wherein the chiral inducing agent    is (+)-N-methylephederin.-   22. The method of embodiment 20, wherein the reaction is carried out    in the presence of a base and a zinc reagent.-   23. The method of embodiment 22, wherein the base is triethylamine.-   24. The method of embodiment 22, wherein the zinc reagent is zinc    triflate.-   25. The method of embodiment 15, wherein P₂ is    tert-butyldimethylsilyl (TBDMS).-   26. The method of embodiment 15, wherein for step (2), the compound    of structural formula (II) is converted to the compound of    structural formula (III) through a cobalt-mediated cyclization    reaction.-   27. The method of embodiment 26, wherein the cobalt-mediated    cyclization reaction is carried out in the presence of CO₂(CO)₈.-   28. The method of embodiment 15, wherein the hydrogenation reaction    of step (3) is carried out in the presence of a base.-   29. The method of embodiment 28, wherein the base is K₂CO₃.-   30. The method of embodiment 15, wherein the reducing agent in    step (4) is NaBH₄.-   31. The method of embodiment 15, wherein for step (5), the compound    of structural formula (V) is deprotected in the presence of an acid.-   32. The method of embodiment 31, wherein the acid is TsOH.-   33. The method of embodiment 15, wherein for step (6), the compound    of structural formula (VI) is reacted with nBuLi and Ph₂PH.-   34. The method of embodiment 15, wherein for step (7), X₁ is —Cl.-   35. The method of embodiment 15, wherein for step (8), the compound    of structural formula (VIII) is hydrolyzed in the presence of a    base.-   36. The method of embodiment 35, wherein the base is NaOH.-   37. The method of embodiment 15, wherein the compound produced by    the method is a sodium salt or a diethanolamine salt of    treprostinil.-   38. The method of embodiment 15, wherein R is (CH₂)_(m)CO₂R₁,    wherein R₁ is an alkyl or a substituted or unsubstituted benzyl    group.-   39. The method embodiment 38, further comprising:    -   (a) reacting the compound of structural formula (A) with a        second alcohol protecting group to form a compound represented        by structural formula (4):

and

-   -   (b) converting the compound of structural formula (4) to a        tricyclic compound represented by structural formula (5):

-   40. The method of embodiment 39, wherein P₂ is    tert-butyldimethylsilyl (TBDMS), tertiarybutyldiphenylsilyl (TBDPS),    triethylsilyl (TES) or triphenylmethyl (trityl group).-   41. The method of embodiment 40, wherein P₂ is    tert-butyldimethylsilyl (TBDMS).-   42. The method of embodiment 39, wherein P₁ is tetrahydrofuranyl    (THP), benzyl, 2,4-dinitrobenzyl, methoxymethyl (MOM),    tertiarybutyldimethylsilyl (TBDMS), tertiarybutyldiphenylsilyl    (TBDPS) or triethylsilyl (TES).-   43. The method of embodiment 42, wherein P₁ is THP.-   44. The method of embodiment 39, wherein m is 1.-   45. The method of embodiment 39, wherein for the converting step    (b), the compound of structural formula (4) is converted to the    compound of structural formula (5) through a cobalt-mediated    cyclization reaction.-   46. The method of embodiment 45, wherein the cobalt-mediated    cyclization reaction is carried out in the presence of CO₂(CO)₈.-   47. The method of embodiment 39, wherein R₁ is an alkyl group and    wherein the method further comprises:    -   (c) hydrogenating the tricyclic compound of structural        formula (5) to form a hydrogenated tricyclic compound        represented by structural formula (6):

and

-   -   (d) converting the hydrogenated tricyclic compound represented        by structural formula (6) to a compound represented by        structural formula (IX):

wherein said converting (d) accomplishes cleaving of the protectivegroup P₁ and ester hydrolysis of R in a single pot.

-   48. The method of embodiment 47, wherein the hydrogenation reaction    of step (c) is carried out in the presence of a base.-   49. The method of embodiment 48, wherein the base is K₂CO₃.-   50. The method of embodiment 47, wherein R₁ is straight or branched    C1-C5 alkyl.-   51. The method of embodiment 50, wherein R₁ is methyl.-   52. The method of embodiment 39, wherein R₁ is a substituted or    unsubstituted benzyl group and wherein the method further comprises:    -   (c′) hydrogenating the tricyclic compound of structural        formula (5) to form a hydrogenated tricyclic compound        represented by structural formula (6′):

and

-   -   (d′) converting the hydrogenated tricyclic compound represented        by structural formula (6′) to a compound represented by        structural formula (IX):

-   53. The method of embodiment 52, wherein the hydrogenation reaction    of step (c) is carried out in the presence of a base.-   54. The method of embodiment 53, wherein the base is K₂CO₃.-   55. The method of embodiment 52, wherein R₁ is an unsubstituted    benzyl group.-   56. The method of embodiment 14, further comprising reacting    compound represented by formula (1):

to form the compound represented by the structural formula

-   57. A compound of formula (1):

wherein R is (CH₂)_(m)CO₂R₁, m is 1, 2 or 3, and

-   -   R₁ is an alkyl group, THP, TBDMS or a substituted or        unsubstituted benzyl group.

-   58. The compound of embodiment 57, wherein m is 1.

-   59. The compound of embodiment 57, wherein R₁ is straight or    branched C1-C5 alkyl.

-   60. The compound of embodiment 59, where R₁ is methyl.

-   61. The compound of embodiment 57, wherein R₁ is unsubstituted    benzyl.

-   62. A compound represented by structural formula (A):

wherein:

-   -   P₁ is an alcohol protecting group;    -   wherein R is (CH₂)_(m)CO₂R₁, m is 1, 2 or 3, and    -   R₁ is an alkyl group or a substituted or unsubstituted benzyl        group.

-   63. The compound of embodiment 62, wherein m is 1.

-   64. The compound of embodiment 62, wherein R₁ is straight or    branched C1-C5 alkyl.

-   65. The compound of embodiment 64, where R₁ is methyl.

-   66. The compound of embodiment 62, wherein R₁ is unsubstituted    benzyl.

-   67. The compound of embodiment 62, wherein P₁ is tetrahydrofuranyl    (THP), benzyl, 2,4-dinitrobenzyl, methoxymethyl (MOM),    tertiarybutyldimethylsilyl (TBDMS), tertiarybutyldiphenylsilyl    (TBDPS) or triethylsilyl (TES).

-   68. The compound of embodiment 76, wherein P₁ is THP.

-   69. A compound represented by structural formula (4):

wherein:

each of P₁ and P₂ is an alcohol protecting group;

wherein R is (CH₂)_(m)CO₂R₁, m is 1, 2 or 3, and

R₁ is an alkyl group, or a substituted or unsubstituted benzyl group.

-   70. The compound of embodiment 69, wherein m is 1.-   71. The compound of embodiment 69, wherein R₁ is straight or    branched C1-C5 alkyl.-   72. The compound of embodiment 71, where R₁ is methyl.-   73. The compound of embodiment 62, wherein R₁ is unsubstituted    benzyl.-   74. The compound of embodiment 62, wherein P₂ is    tert-butyldimethylsilyl (TBDMS), tertiarybutyldiphenylsilyl (TBDPS),    triethylsilyl (TES) or triphenylmethyl (trityl group).-   75. The compound of embodiment 67, wherein P₂ is    tert-butyldimethylsilyl (TBDMS).-   76. The compound of embodiment 69, wherein P₁ is tetrahydrofuranyl    (THP), benzyl, 2,4-dinitrobenzyl, methoxymethyl (MOM),    tertiarybutyldimethylsilyl (TBDMS), tertiarybutyldiphenylsilyl    (TBDPS) or triethylsilyl (TES).-   77. The compound of embodiment 76, wherein P₁ is THP.-   78. A compound represented by structural formula (5):

wherein:

each of P₁ and P₂ is an alcohol protecting group;

wherein R is (CH₂)_(m)CO₂R₁, m is 1, 2 or 3, and

R₁ is an alkyl group, or a substituted or unsubstituted benzyl group.

-   79. The compound of embodiment 78, wherein m is 1.-   80. The compound of embodiment 78, wherein R₁ is straight or    branched C1-C5 alkyl.-   81. The compound of embodiment 80, where R₁ is methyl.-   82. The compound of embodiment 78, wherein R₁ is unsubstituted    benzyl.-   83. The compound of embodiment 78, wherein P₂ is    tert-butyldimethylsilyl (TBDMS), tertiarybutyldiphenylsilyl (TBDPS),    triethylsilyl (TES) or triphenylmethyl (trityl group).-   84. The compound of embodiment 83, wherein P₂ is    tert-butyldimethylsilyl (TBDMS).-   85. The compound of embodiment 78, wherein P₁ is tetrahydrofuranyl    (THP), benzyl, 2,4-dinitrobenzyl, methoxymethyl (MOM),    tertiarybutyldimethylsilyl (TBDMS), tertiarybutyldiphenylsilyl    (TBDPS) or triethylsilyl (TES).-   86. The compound of embodiment 85, wherein P₁ is THP.-   87. A compound represented by structural formula (6):

wherein:

P₁ is an alcohol protecting group;

wherein m is 1, 2 or 3, and

R₁ is an alkyl group, or hydrogen.

-   88. The compound of embodiment 87, wherein m is 1.-   89. The compound of embodiment 87, wherein R₁ is straight or    branched C1-C5 alkyl.-   90. The compound of embodiment 89, where R₁ is methyl.-   91. The compound of embodiment 87, wherein R₁ is unsubstituted    benzyl.-   92. The compound of embodiment 87, wherein P₁ is tetrahydrofuranyl    (THP), benzyl, 2,4-dinitrobenzyl, methoxymethyl (MOM),    tertiarybutyldimethylsilyl (TBDMS), tertiarybutyldiphenylsilyl    (TBDPS) or triethylsilyl (TES).-   93. The compound of embodiment 92, wherein P₁ is THP.

Although the foregoing refers to particular preferred embodiments, itwill be understood that the present invention is not so limited. It willoccur to those of ordinary skill in the art that various modificationsmay be made to the disclosed embodiments and that such modifications areintended to be within the scope of the present invention.

All of the publications, patent applications and patents cited in thisspecification are incorporated herein by reference in their entirety.

1. A method of preparing a compound represented by the followingstructural formula:

comprising reacting a compound represented by the following structuralformula:

with a compound represented by the following structural formula:

wherein: P₁ is an alcohol protecting group; R is —(CH₂)₁X; X is H,phenyl, —CN, —OR₁ or COOR₁; R₁ is an alkyl, THP, TBDMS or aunsubstituted or substituted benzyl group; and n is 1, 2 or
 3. 2. Themethod of claim 1, wherein R is (CH₂)_(n)COOR₁, wherein R₁ is an alkylor a unsubstituted or substituted benzyl group.
 3. The method of claim2, wherein R₁ is C1-C5 alkyl.
 4. The method of claim 2, wherein R₁ isbenzyl.
 5. The method of claim 1, wherein P₁ is tert-butyldimethylsilyl(TBDMS), tertiarybutyldiphenylsilyl (TBDPS), triethylsilyl (TES) ortriphenylmethyl (trityl group).
 6. The method of claim 5, wherein P₁ istert-butyldimethylsilyl (TBDMS).
 7. The method of claim 1, wherein thereaction is carried out in the presence of chiral inducing agent.
 8. Themethod of claim 7, wherein the chiral inducing ligand is(+)-N-methylephederin.
 9. The method of claim 1, wherein the reaction iscarried out in the presence of a base and a zinc reagent.
 10. A methodof preparing a compound represented by the following structural formula:

or a pharmaceutically acceptable salt thereof, comprising: reacting acompound represented by structural formula (I):

with a compound represented by structural formula (a):

to form a compound represented by structural formula (A):

wherein: P₁ is an alcohol protecting group; R is —(CH₂)_(m)X; X is H,phenyl, —CN, —OR₁ or COOR₁; R₁ is an alkyl group, THP, TBDMS or asubstituted or unsubstituted benzyl group; and m is 1, 2 or
 3. 11. Themethod of claim 10, further comprising: (1) reacting the compound ofstructural formula (A) with an alcohol protecting group to form acompound represented by structural formula (II):

(2) converting the compound of structural formula (II) to a tricycliccompound represented by structural formula (III):

(3) hydrogenating the tricyclic compound of structural formula (III) toform a hydrogenated tricyclic compound represented by structural formula(IV):

(4) reacting the compound of structural formula (IV) with a reducingagent to form a compound represented by structural formula (V):

(5) deprotecting the compound of structural formula (V) to form acompound represented by structural formula (VI):

(6) converting the compound represented by structural formula (VI) to acompound represented by structural formula (VII):

(7) reacting the compound represented by structural formula (VII) withX₁(CH₂)_(m)CN to form a compound represented by structural formula(VIII):

and (8) hydrolyzing the compound of Structural Formula (VIII) to formthe compound represented by Structural Formula (IX), wherein: P₂ is analcohol protecting group; m is 1, 2 or 3; and X₁ is a leaving group. 12.The method of claim 10, wherein R is (CH₂)_(m)CO₂R₁, wherein R₁ is analkyl or a substituted or unsubstituted benzyl group.
 13. The methodclaim 12, further comprising: (a) reacting the compound of structuralformula (A) with a second alcohol protecting group to form a compoundrepresented by structural formula (4):

and (b) converting the compound of structural formula (4) to a tricycliccompound represented by structural formula (5):


14. The method of claim 13, wherein P2 is tert-butyldimethylsilyl(TBDMS), tertiarybutyldiphenylsilyl (TBDPS), triethylsilyl (TES) ortriphenylmethyl (trityl group).
 15. The method of claim 14, wherein P2is tert-butyldimethylsilyl (TBDMS).
 16. The method of claim 13, whereinP1 is tetrahydrofuranyl (THP), benzyl, 2,4-dinitrobenzyl, methoxymethyl(MOM), tertiarybutyldimethylsilyl (TBDMS), tertiarybutyldiphenylsilyl(TBDPS) or triethylsilyl (TES).
 17. The method of claim 16, wherein P1is THP.
 18. The method of claim 13, wherein for the converting step (b),the compound of structural formula (4) is converted to the compound ofstructural formula (5) through a cobalt-mediated cyclization reaction.19. The method of claim 18, wherein the cobalt-mediated cyclizationreaction is carried out in the presence of Co2(CO)8.
 20. The method ofclaim 13, wherein R1 is an alkyl group and wherein the method furthercomprises: (c) hydrogenating the tricyclic compound of structuralformula (5) to form a hydrogenated tricyclic compound represented bystructural formula (6):

and (d) converting the hydrogenated tricyclic compound represented bystructural formula (6) to a compound represented by structural formula(IX):

wherein said converting (d) accomplishes cleaving of the protectivegroup P₁ and ester hydrolysis of R in a single pot.
 21. The method ofclaim 20, wherein the hydrogenation reaction of step (c) is carried outin the presence of a base.
 22. The method of claim 21, wherein the baseis K2CO3.
 23. The method of claim 20, wherein R1 is straight or branchedC1-C5 alkyl.
 24. The method of claim 23, wherein R1 is methyl.
 25. Themethod of claim 13, wherein R1 is a substituted or unsubstituted benzylgroup and wherein the method further comprises: (c′) hydrogenating thetricyclic compound of structural formula (5) to form a hydrogenatedtricyclic compound represented by structural formula (6′):

and (d′) converting the hydrogenated tricyclic compound represented bystructural formula (6′) to a compound represented by structural formula(IX):


26. The method of claim 25, wherein the hydrogenation reaction of step(c) is carried out in the presence of a base.
 27. The method of claim26, wherein the base is K2CO3.
 28. The method of claim 25, wherein R1 isan unsubstituted benzyl group.
 29. The method of claim 13, furthercomprising reacting compound represented by formula (1):

to form the compound represented by the structural formula


30. The method of claim 13, wherein m=1.